Hypersensitivity Reactions

Type I/Allergic /Immediate Hypersensitivity(IgE)- rapid immunologic reaction occurring within minutes after combination of antigen with
antibody bound to mast cells in individuals previously sensitized to the Ag.The systemic reaction usually follows injection of an antigen to which the host
has become sensitized. The nature of local reactions varies depending on the portal of entry of the allergen and may take the form of localized cutaneous
swellings (skin allergy, hives), nasal and conjunctival discharge (allergic rhinitis and conjunctivitis), hay fever, bronchial asthma, or allergic gastroenteritis
(food allergy).
These have two well-defined phases:-
The immediate, or initial, response is characterized by vasodilation, vascular leakage, and depending on the location,
smooth muscle spasm or glandular secretions. These changes usually become evident within 5 to 30 minutes after exposure to an allergen and tend to subside
in 60 minutes.
Second, late-phase reaction sets in 2 to 24 hours later without additional exposure to antigen and may last for several days. This is characterized by
infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells as well as tissue destruction, in the form of mucosal damage.
Events:

Exposure to AgDendritic cells present Ag toNave CD4+ helper T cellsT cells differentiate to TH2 cellsTH2 cells

Local cytokines like IL4
Produce cytokines on further
exposure to Ag( IL-4,IL-5,IL-13)


IL-4 Acts on B cells to stim. class switching to IgE, development of additional TH2 cells
IL-5 Development & activation of eosinophils
IL-13 IgE production, mucus secretion


Mast cells & Basophils have FcRI receptor specific for Fc portion of IgE
therefore bind IgE

Mast cell with IgE exposed to AgAg binds to IgE on mast cellBridging of Fc receptors


Mast cell degranulation & release of
Primary/preformed mediators & de novo synthesis of
Secondary mediators.

Preformed mediators lead to immediate phase & consist of:
Vasoactive amines- Histamine( smooth ms contraction, Vs permeability, mucus secretion by glands)
Enzymes- Neutral proteases(chymase, tryptase), Acid hydrolasecause tissue damage, generate kinins & activate complement by
enzymatic axn.
Proteoglycans- Heparin, Chondroitin sulfateanticoagulent, packaging & storage of amines in granules.
Lipid mediators- derived from membrane phospholipids Arachidonic acid
Leukotrienes- LTC4 & LTD4 most potent vasoactive & spasmogenic agents known; LTB4 chemotactic for neutrophils,
eosinophils & monocytes.
Prostaglandin D2 -- most abundant mediator produced by COX; Causes bronchospasm & mucus secretion.
Platelet Activating Factor (PAF) platelet aggregation, histamine release, bronchospasm, Vs permeability, Vasodilation,
chemotaxis of neutrophils & eosinophils. PAF is not derived from Arachidonic acid.
Cytokines- Include:
TNF, IL-1 promote leukocyte recruitment typical of late- phase reaction.
Chemokines
IL-4 amplifies TH2 response. Etc

Systemic TypeI hypersensitivityAnaphylaxis
Local TypeI hypersensitivity Eczema, Hay fever, Atopic Asthma

Other examples of TypeI hypersensitivity Theoblad Smith phenomenon( anaphylaxis in guinea pigs)
Prusnitz Kunster reaction(PK rxn), Casonis test.
Other stimuli for Mast cells:
Complement components like
C5a,C3a k/a anaphylotoxins
Chemokines like IL-8
Drugs- codeine, morphine,
adenosine, bee venom
Physical stimuli- heat, cold,
sunlight

Type II/ Antibody mediated Hypersensitivity reaction(IgG & IgM) -- Also k/a cytotoxic/complement mediated lysis caused
by antibodies which react with Ag present on cell surface or extracellular matrix. Three different antibody-dependent mechanisms involved in this type
of reaction are :-
Opsonization and Phagocytosis -- The cells are coated (opsonized) with molecules that make them attractive for phagocytes. When
Ab are deposited on the surfaces of cells, they may activate the complement system (if IgM or IgG class). Complement activation generates
byproducts, mainly C3b and C4b, which are deposited on the surfaces of the cells and recognized by phagocytes that express receptors for
these proteins. In addition, cells opsonized by IgG antibodies are recognized by phagocyte Fc receptors, which are specific for the Fc portions.
The net result is the phagocytosis of the opsonized cells and their destruction. Complement activation on cells also leads to the formation of
the membrane attack complex, which disrupts membrane integrity by "drilling holes" through the lipid bilayer, thereby causing osmotic lysis
of the cells.
Antibody-mediated destruction of cells may occur by another process called antibody-dependent cellular cytotoxicity (ADCC).
Cells that are coated with low concentrations of IgG antibody are killed by a variety of effector cells, which bind to the target by their
receptors for the Fc fragment of IgG, and cell lysis proceeds without phagocytosis. ADCC may be mediated by monocytes, neutrophils,
eosinophils, and NK cells.
Complement- and Fc Receptor-Mediated Inflammation Ab deposit in extracellular tissues, such as basement
membranes and matrix, the resultant injury is because of inflammation and not because of phagocytosis or lysis of cells. The deposited
antibodies activate complement, generating byproducts, such as C5a, that recruit neutrophils and monocytes. The same cells also bind to the
deposited Ab via their Fc receptors. The leukocytes are activated, they release injurious substances, such as enzymes and reactive oxygen
intermediates, and the result is damage to the tissues. Inflammation in antibody-mediated (and immune complex-mediated) diseases is
because of both complement and Fc receptordependent reactions.
Antibody-Mediated Cellular Dysfunction -- In some cases, antibodies directed against cell-surface receptors impair or
dysregulate function without causing cell injury or inflammation. For example :
Increased function Graves disease
Decreased function Myaesthenia gravis

Examples :-
Opsonization and Phagocytosis Blood transfusion reaction, Erythroblastosis fetalis, Autoimmune haemolytic anemia, Autoimmune
thrombocytopenic purpura, Agranulocytosis, Thrombocytopenia, some drug reactions.
Complement- and Fc Receptor-Mediated Inflammation Some forms of glomerulonephritis, Vascular rejection in organ grafts, Vasculitis
caused by ANCA, Goodpasture syndrome, Acute rheumatic fever.
Ab mediated cellular dysfunction Myaesthenia gravis, Graves disease, Pemphigus vulgaris.

Type III/ Immune complex mediated hypersensitivity reaction(IgM & IgG) Ag-Ab complexes produce tissue damage mainly by
eliciting inflammation at site of deposition. Ag which form complexes may be exogenous, like foreign protein that is injected or produced by microbe,
or endogenous, if Ab is against self Ag as in auto immune disorders.
Immune complex-mediated diseases can be generalized, if immune complexes are formed in the circulation and are deposited in many
organs, or localized to particular organs, such as the kidney (glomerulonephritis), joints (arthritis), or the small blood vessels of the skin if the
complexes are formed and deposited locally.
Systemic Immune Complex Disease - Acute serum sickness is the prototype of a systemic immune complex disease; it was at one time a
frequent sequela to the administration of large amounts of foreign serum. The pathogenesis of systemic immune complex disease can be divided into
three phases:
1. Formation of Immune Complexes -- The introduction of a protein antigen triggers an immune response that results in the formation
of antibodies, typically about a week after the injection of the protein. These antibodies are secreted into the blood, where they react with the
antigen still present in the circulation and form antigen-antibody complexes.
2. Deposition of Immune Complexes -- In the next phase the circulating antigen-antibody complexes are deposited in various tissues.
Complexes that are of medium size, formed in slight antigen excess, are the most pathogenic. Organs where blood is filtered at high pressure
to form other fluids, like urine and synovial fluid, are favored; hence, immune complexes frequently deposit in glomeruli and joints.
3. Tissue Injury Caused by Immune Complexes -- Once complexes are deposited in the tissues, they initiate an acute inflammatory
reaction (the third phase). During this phase (approximately 10 days after Ag administration), clinical features such as fever, urticaria,
joint pains (arthralgias), lymph node enlargement, and proteinuria appear. Wherever complexes deposit the tissue damage is similar. The
resultant inflammatory lesion is termed vasculitis if it occurs in blood vessels, glomerulonephritis if it occurs in renal glomeruli, arthritis if it
occurs in the joints, and so on.
It is clear that complement-fixing antibodies (i.e., IgG and IgM) and antibodies that bind to leukocyte Fc receptors (some subclasses of IgG) induce
the pathologic lesions of immune-complex disorders. The principal morphologic manifestation of immune complex injury is acute necrotizing vasculitis,
with necrosis of the vessel wall and intense neutrophilic infiltration. The necrotic tissue and deposits of immune complexes, complement, and plasma
protein produce a smudgy eosinophilic deposit that obscures the underlying cellular detail, an appearance termed fibrinoid necrosis. If the disease
results from a single large exposure to antigen (e.g., acute serum sickness), the lesions tend to resolve, as a result of catabolism of the immune
complexes. A chronic form of serum sickness results from repeated or prolonged exposure to an Ag. This occurs in several human diseases, such as
SLE.
Local Immune Complex Disease (Arthus Reaction)
The Arthus reaction is a localized area of tissue necrosis resulting from acute immune complex vasculitis, usually elicited in the skin. The reaction
can be produced experimentally by intracutaneous injection of antigen in a previously immunized animal that contains circulating antibodies against
the antigen. As the antigen diffuses into the vascular wall, it binds the preformed antibody, and large immune complexes are formed locally. These
complexes precipitate in the vessel walls and cause fibrinoid necrosis, and superimposed thrombosis.

Examples of Type III rxn :-- Shicks test, Post streptococcal GN, SLE, PAN, Reactive Arthritis


Type IV/Delayed/ T cell mediated hypersensitivity - initiated by antigen-activated (sensitized) T lymphocytes, including CD4+ and
CD8+ T cells. CD4+ T cellmediated hypersensitivity induced by environmental and self-antigens can be a cause of chronic inflammatory disease.
In certain forms of T cell mediated reactions, especially those that follow viral infections, CD8+ cells may be the dominant effector cells.

Reactions of CD4+ T Cells: Delayed-Type Hypersensitivity and Immune Inflammation
Inflammatory reactions caused by CD4+ T cells are seen in delayed-type hypersensitivity (DTH) to exogenously administered antigens & chronic
inflammatory reactions against self-tissues. It is sometimes referred to as immune inflammation. Both TH1 and TH17 cells contribute, reaction
associated with TH1 cells is dominated by activated macrophages, and that triggered by TH17 cells has a greater neutrophil component. The
reactions can be divided into the following stages.
Proliferation and Differentiation of CD4+ T Cells- Naive CD4+ T cells recognize peptides displayed by dendritic cells and
secrete IL-2, which functions as an autocrine growth factor to stimulate proliferation of the antigen-responsive T cells. The subsequent
differentiation of antigen-stimulated T cells to TH1 or TH17 cells is driven by the cytokines produced by APCs at the time of T-cell
activation. If APCs (dendritic cells and macrophages) produce IL-12, which induces differentiation of CD4+ T cells to the TH1 subset.
If the APCs produce inflammatory cytokines such as IL-1, IL-6, IL-23, in collaboration with TGF- to stimulate differentiation of T
cells to the TH17 subset. Some of the differentiated effector cells enter the circulation and may remain in the memory pool of T cells for long
periods, sometimes years.
Responses of Differentiated Effector T Cells - Upon repeat exposure to an Ag, previously activated T cells recognize the Ag
displayed by APCs and respond. TH1 cells secrete cytokines, mainly IFN- .IFN-activated macrophages are altered in several ways:
their ability to phagocytose and kill microorganisms is markedly augmented; they express more class II MHC molecules on the surface,
thus facilitating further Ag presentation; they secrete TNF, IL-1, and chemokines, which promote inflammation; and they produce more
IL-12, thereby amplifying the TH1 response. Thus, activated macrophages serve to eliminate the offending Ag; if the activation is
sustained, continued inflammation and tissue injury result.
TH17 cells are activated by some microbial antigens and by self-antigens in autoimmune diseases. Activated TH17 cells secrete
IL-17, IL-22, chemokines,etc. Collectively, these cytokines recruit neutrophils and monocytes to the reaction, thus promoting inflammation.
TH17 cells also produce IL-21, which amplifies the TH17 response.
Examples of DTH - tuberculin reaction, Contact dermatitis

Reactions of CD8+ T Cells: Cell-Mediated Cytotoxicity - In this type of T cellmediated reaction, CD8+ CTLs kill antigen-
bearing target cells. CTLs directed against cell surface Ag play an important role in graft rejection, type 1 DM, virus-infected cell(viral hepatitis),
tumors. The principal mechanism of T cellmediated killing of targets involves perforins and granzymes, preformed mediators contained in the
lysosome-like granules of CTLs. CTLs that recognize the target cells secrete a complex consisting of perforin, granzymes, and a protein called
serglycin, which enters target cells by endocytosis. In the target cell cytoplasm, perforin facilitates the release of the granzymes from the complex.
Granzymes are proteases that cleave and activate caspases, which induce apoptosis of the target cells. Activated CTLs also express Fas ligand, a
molecule with homology to TNF, which can bind to Fas expressed on target cells and trigger apoptosis. CD8+ T cells also produce cytokines,
notably IFN-, and are involved in inflammatory reactions resembling DTH, especially following virus infections and exposure to some contact
sensitizing agents.

Examples of Type IV hypersensitivityTuberculin test, Lepromin test, Contact dermatitis, Graft rejection(chronic), Jones-Mote reaction(cutaneous
basophilic hypersensitivity), Type 1 DM, Multiple sclerosis, rheumatoid arthritis, Crohns disease, Peripheral neuropathy;Guillain-Barre syndrome?